basic immunology - immbio.hu
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Basic ImmunologyLecture 1st and 2nd
IntroductionRequirements of the Department.
Historical overview. Composition of the immune system.
Molecular components of theimmune systemes
Immunological recognition in innate, adaptive, and naturalimmunity. Definition of the antigen. Molecular structures
of immunoglobulins, T-cell and B-cell receptors.
Requirements and information• Lectures: 14 hours (participation is obligatory, importance of
the preparation of own lecture notes), no more abscences as 3!
• Practices: 14 hours laboratory practices & seminars.
No more absences as 3!
• Bonus points: 10 times 2-2 questions from the lectures and seminars/practices. Minimum requirement is 5 points for acceptance of semester. All points are plus 1 to the exam scores after the 10 basic points .
• Collection of extra points is available during lectures.
• Examination: written from the lectures and laboratory practices/seminars
• Exam scores: (minimum level: 66%) satisfactory 66-71%, average 72- 77%, good 78-83%, excellent 84%
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What is the immune system?
• The immune system is a complex NETWORK composed
by molecular and cellular elements.
• The main function of the immune system is managing
of the individual integrity with defence against outside
parasites and against modifications of self structures
(by viral infections, tumorous transformations or other
mutations).
• The immune network is formed by balance of attacking
and tolerating type immune responses.
• The immune system links to the other (endocrine,
neural, metabolic) regulatory systems of the body in
multiple levels influencing each other.
Basic terms
• Immunis,- e (Julius Caesar) = exempt, free of burden (E.g. tax, law, or diseases)
• IMMUNE: individuals who do not capitulate to a disease when infected;
• IMMUNITY: status of specific resistance to a disease;
• IMMUNOLOGY: branch of theoretical biology focuses on mechanisms responsible for both self and non-self recognition, elimination of the invaders and protection of the basic structural elements.
History• Athen (B.C. 5th century Thukidites - plaque survivors),
ancient Chinese papers about the pox immunity
• Infections, epidemies, vaccination
Edward Jenner Louis Pasteur
(1749 - 1823) (1822 - 1895)
Edward Jenner (1749 - 1823)• He was a doctor in Berkeley, Gloucestershire. In 1796 he
carried out his now famous experiment on eight-year-old James Phipps. Jenner inserted pus taken from a cowpox pustule on the hand of milkmaid Sarah Nelmes and inserted it into an incision on the boy's arm. He was testing his theory, drawn from the folklore of the countryside, that milkmaids who suffered the mild disease of cowpox never contracted smallpox.
• Jenner subsequently proved that having been inoculated with cowpox Phipps was now immune to smallpox. He submitted a paper to the Royal Society in 1797 describing his experiment but was told that his ideas were too revolutionary and that he needed more proof. Undaunted, Jenner experimented on several other children, including his own 11-month-old son. In 1798 the results were finally published and Jenner coined the word vaccine from the Latin vacca for cow, and called the process vaccination.
THE NOBEL PRIZE LAUREATES IN IMMUNOLOGY1901 E.A. Von Behring (Germany) for the work on serum therapy especially its application against diphtheria.
1905 R. Koch (Germany) for the investigations concerning tuberculosis.
1908 E. Metchnikoff (Russia) and P. Ehrlich (Germany) for their work on immunity (respectively, phagocytosis/cellular theory and humoral theory).
1913 C.R. Richet (France) for the work on anaphylaxis.
1919 J. Bordet (Belgium) for the discoveries relating to immunity (complement).
1930 K. Landsteiner (Austria/USA) for the discovery of human blood groups.
1951 M. Theiler (South Africa) for the discoveries and developments concerning yellow fever.
1957 D. Bovet (Italy/Switzerland) for the discoveries related to histamine and compounds, which inhibit action of histamine and other substances on the vascular system and the skeleton muscles.
1960 Sir F.McFarlane Burnet (Australia) and Sir P.B. Medawar (Great Britain) for the discovery of acquired immunological tolerance.
1972 G.M. Edelman (USA) and R.R. Porter (Great Britain) for their discovery concerning the chemical structure of antibodies.
1977 R. Yalow (USA) for the development of radioimmunoassays of peptide hormones.
1980 B. Benacerraf (USA), J. Dausset (France) and G.D. Snell (USA) for their discoveries concerning genetically determined structures on the cell surface (major histocompatibility complex) that regulate immunological reactions.
1982 S. K. Bergstrom (Sweden), B. I. Samuelsson (Sweden) and J. R. Vane (UK) for their discoveries concerning prostaglandins and related biologically active substances.
1984 N.K. Jerne (Denmark/Switzerland) for theories concerning the specificity in development (lymphocyte clonality) and control of the immune system; G.J.F. Köhler (Germany/Switzerland) and C. Milstein(Argentina/Great Britain) for the discovery of the principle for production of monoclonal antibodies.
1987 S. Tonegawa (Japan/USA) for the discovery of the genetic principle for generation of antibody diversity.
1990 J.E. Murray and E.D. Thomas (USA) for their discovery concerning organ and cell transplantation in the treatment of human diseases.
1996 P.C. Doherty (Australia/USA) and R.M. Zinkernagel (Switzerland) for their discoveries concerning the specificity of the cell mediated immune defense ("dual recognition").
1997 S.B. Prusiner (USA) for the discovery of prions as a new biological principle of infection.
1999 G. Blobel (USA) for discoveries concerning signal transduction.
Immune system
– Individuals and species
– Organs
– Cells
– Molecules
– Functions
Structural and functional network
Composition of the immune system
Natural
Innate-like immunity with adaptive features
Innate
•None antigen specific
•No immunological memory
•Rapid reactivity
•Linear amplification of the
reaction
Adaptive
•Antigen specific
•Immunological memory
•Activated after a latency
•Exponential amplification of
the reaction
Innate immune system Pattern recognition receptors (PRR)
Pathogen associated molecular patterns (PAMP)
First line defence
Low number of molecularly distinct receptors
and high number of recognized patterns
Main molecular components: Antibacterial
peptides, Complement factors and their receptors, Heat
shock proteins, Fc receptors, Inflammatory cytokines,
Growth factors, Histamine
Main cellular components: Macrophages,
Monocytes, NK cells, Granulocytes, Mast cells
Adaptive immune system
Antigen receptor (BCR,TCR)
Epitope specific in a given antigen
Adaptive immune response
High number of distinct antigen receptors and
high number of recognized antigens
Main molcelar components: Antibodies, MHC, T
and B cell receptors, Lymphatic citokines
Main cellular components: T cells (both αβ and
γδ), B cells, Antigen presenting cells
Natural immune system
Antigen recognition receptors (BCR,TCR) with
limited specificity
Patern recognition profile
Innate-like immune response
Limited number of distinct antigen receptors and
high number of recognized antigens
Main cellular components: iNKT cells, iγδT cells,
MAIT cells, IEL cells, CD5+ B cells
Main molcelar components: natural (auto)antibodies
Theoretical scheme of the innate immunity
SIGNAL
RECOGNITION RESPONSE
Theoretical scheme of the adaptive immunity
SIGNAL
RECOGNITION DIFFERENTIATION EFFECTOR FUNCTIONS
MEMORY
Definition of the antigenDetre (Deutsch) László (1874-1939):
ANTIBODY GENERATOR: foreign substance induces antibody production(1899)
Modern definition: substance, which is recognized by T cell and/or B cell receptors, and it is able to induce active immune response or toleranceaccording to the host immunogenetic background (MHC haplotype).
Factors determining the immunogenity
• immunodominant regions
• chemical structure (inorganic molecules are not antigens at general, but e.g. heavy metals in protein complex are able to induce specific metal allergies). The best antigens are proteins>polypeptides>polysaccharides>lipides>nucleic acids
• physico-chemical nature (D and L configuration; ortho-, para,- meta position; hydrophilic and hydrophobic amino acid sequence)
• molecular weight (not an absolute category)
• conformation sensitivity (folding and refolding)
• Origin auto-, allo-, xenoantigen
• mode and anatomic region of the administration (e.g. peripheral immune reaction and oral tolerance for the same antigen depending from the place of the antigen presentation)
• dose dependence (large and low dose)
• Valency: monovalent, bivalent, and multivalent antigens
Recognition molecules in the
adaptive immune system
Immunoglobulins
B cell receptors (BcR)
T cell receptors (TcR)
MHC class I and class II
Specialized molecules manage antigen recognition.
The common structural features of these molecules
are the well-conserved (constant) basic elements
(designed by 110 amino acids domain units)
containing variable, antigen specific parts (binding
sites) for the recognition and ligand formation.
Domain structure
Well conserved amino acid sequence designed by 110 amino acids
closed to a “ring shape” with disulphide bound.
Immunoglobulin molecule
CDR
Variable region
Idiotype
Fab fragment
Constant region
Isotype
Fc fragment
Ig domains: intra-chain disulphide
bonds form loops in the peptide
chain, the loops are globular,
constructed from beta-plated
sheets and beta-turn loops.
Immunoglobulins
Monofunctional character (specific antigen
recognition and binding) before the antigen
administration. Fab dependent function.
Polyfunctional character after the
antigen administration (signal transduction,
complement fixation, opsonization,
immunocomplex formation, FcR binding, etc).
Fc dependent functions.
Immunoglobulin isotypes
• Based upon the constant structures of heavy
(H) and light (L) chains
• CH isotypes: called Ig classes and
subclasses as IgG, IgM, IgA, IgD and IgE.
All classes are represented in a normal
serum (except the membrane bound IgD) as
isotype variants.
• CL chain exists in two isotypic forms:
kappa (κ) and lambda (λ), which can
associate with all heavy chain isotypes.
Immunoglobulin idiotypeIndividual determinants in V
regions, specific for each
antibody.
The N terminal Ig domain
contains V region forming
the antigen binding site:
clustering the 3 hyper
variable sequences close to
each other on both chains -
the variation of 3 x 3 results
tremendous diversity.